Pancreatic cancer and Palb2

BACKGROUND: Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging. METHODS: Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features...

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarkers is essential for increasing the viability of precision therapy for pancreatic cancer. METHODS: We collected blood and tumor tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape...

PURPOSE: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets. EXPERIMENTAL DESIGN: PACC specimens (n=51) underwent next-generation sequencing (NGS) of DNA (n=29) or whole exome [n=22]) and RNA (whole transcriptome, n=29) at a commercial laboratory...

UNLABELLED: Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47...

IMPORTANCE: Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed. OBJECTIVE: To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A...

BACKGROUND AND OBJECTIVES: Modest data exist on the benefits of screening and surveillance for pancreatic cancer (PC) in high-risk individuals. Intraductal papillary mucinous neoplasms (IPMN) are known precursors to PC. We hypothesized that patients with high-risk deleterious germline mutations have a higher prevalence of IPMN. METHODS: All patients undergoing prospective screening at a single institution from 2013 to 2019 were reviewed. RESULTS: Of 1166 patients screened, 358 (31%) possessed germline mutations and/or family history of PC (mutations n = 201/358, 56%, family history n = 226/358, 63%) (median follow-up 2...

PURPOSE: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients. METHODS: We analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ)...

PURPOSE: The genetic attribution for pancreatic ductal adenocarcinoma (PDAC) has been reported as 5-10%. However, the incidence of germline pathogenic variants (PVs) in Korean PDAC patients has not been thoroughly investigated. Therefore we studied to identify the risk factors and prevalence of PV for future treatment strategies in PDAC. MATERIALS AND METHODS: Total of 300 (155 male) patients with a median age of 65 years (33-90) were enrolled in National Cancer Center in Korea...

BACKGROUND: Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non-G12C KRAS mutations, and only a small subset of patients are eligible for FDA-approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population. METHODS: To explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants...

UNLABELLED: We investigate the prevalence of germline mutations in cancer predisposition genes in patients with pancreatic ductal adenocarcinoma (PDAC) or suspected related hereditary syndromes. METHODS: we enrolled for NGS with an Illumina TrueSight Cancer panel comprising 19 CPGs and 113 consecutive subjects referred to cancer genetic clinics for metastatic PDAC, early onset PDAC, suspected hereditary syndrome, or positive family history. RESULTS: Overall, 23 (20...

BACKGROUND: Genetic testing for pancreatic ductal adenocarcinoma (PDAC) patients is in constant development. However, the status of homologous recombination repair (HRR) genes in unselected Chinese PDAC has not been fully explored. This study aims to characterize the profile of germline mutations in HRR genes in Chinese PDAC patients. METHODS: A cohort of 256 PDAC patients were enrolled at Zhongshan Hospital Fudan University between 2019 and 2021. Germline DNA was analyzed by next-generation sequencing using a multigene panel of the 21 HRR genes...

INTRODUCTION: National Comprehensive Cancer Network (NCCN) 2019 Guidelines recommend universal germline (GL) testing for patients (pts) with pancreatic cancer (PC), given germline mutations (gMut) can occur at a similar rate irrespective of an individual's family history of cancer. Molecular analysis of tumors in those with metastatic disease is also recommended. We aimed to determine rates of genetic testing at our institution, factors associated with testing, and outcomes of those tested...

The number of cases of pancreatic cancers in 2019 in Poland was 3852 (approx. 2% of all cancers). The course of the disease is very fast, and the average survival time from the diagnosis is 6 months. Only <2% of patients live for 5 years from the diagnosis, 8% live for 2 years, and almost half live for only about 3 months. A family predisposition to pancreatic cancer occurs in about 10% of cases. Several oncogenes in which somatic changes lead to the development of tumours, including genes BRCA1/2 and PALB2, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1, are involved in pancreatic cancer...

Familial pancreatic cancer (FPC) is a rare hereditary tumor entity with broad phenotypic heterogeneity, including colorectal carcinoma (CRC) in some families. The underlying factors for this co-occurrence are still not well evaluated. FPC families in the National Case Collection of Familial Pancreatic Cancer with an additional occurrence of CRC were analyzed regarding the phenotype, genotype and recommendation for a clinical screening program. The total cohort of 272 FPC families included 30 (11%) families with at least one CRC case...

BACKGROUND: Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP). PATIENTS AND METHODS: Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab...

The partner and localiser of BRCA2 (PALB2) gene, located on chromosome 16, functions as a tumour suppressor that plays a critical role in homologous recombination repair after DNA double-strand breaks. It encodes proteins involved in the BRCA2 and BRCA1, and RAD51 pathways. Heterozygous germline mutations in PALB2 have been implicated in the development of breast, pancreatic and ovarian cancers. Whereas biallelic mutations of PALB2 have been associated with Fanconi anaaemia. Currently, 604 distinct PALB2 variants have been discovered...

The aggressive biology of pancreatic ductal adenocarcinoma (PDAC), along with its limited sensitivity to many systemic therapies, presents a major challenge in the management of patients with metastatic PDAC. Over the past decade, the incorporation of combinatorial cytotoxic chemotherapy regimens has improved patient outcomes. Despite these advances, resistance to cytotoxic chemotherapy inevitably occurs, and there is a great need for effective therapies. A major focus of research has been to identify molecularly defined subpopulations of patients with PDAC who may benefit from targeted therapies that are matched to their molecular profile...

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A . However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with ( CDKN2A + ) and without ( CDKN2A- ) GPV...

Recent efforts to personalize treatment with platinum-based chemotherapy and PARP inhibitors have produced promising results in homologous recombinant deficient (HRD) metastatic pancreatic cancer (MPC). However, new strategies are necessary to overcome resistance. The below case series documents patients treated at the HonorHealth Research Institute with a diagnosis of HRD MPC who received Mitomycin C (MMC) treatment from January 2013 until July 2018. Five HRD MPC patients treated with MMC were evaluated. All patients received at least one course of treatment...

BACKGROUND: Partner and localizer of BRCA2 (PALB2) is a pancreatic cancer (PC) susceptibility gene reported in Caucasians. However, limited data are available among Asians. We investigated the contribution of PALB2 germline variants to Pakistani PC patients. METHODS: 150 unselected and prospectively enrolled PC patients were comprehensively screened for PALB2 variants, using denaturing high-performance liquid chromatography and DNA sequencing. Novel variants were investigated for their pathogenic effect using in-silico tools...